Liposomes are used for a variety of therapeutic purposes, in particular, for carrying therapeutic agents to target cells by systemic administration of liposomes.
When liposomes are administered systemically, it is desirable to coat the liposomes with a hydrophilic agent, for example, a coating of hydrophilic polymer chains such as polyethylene glycol, to extend the blood circulation lifetime of the liposomes. An extended circulation time is often needed for liposomes to reach the target region, cell or site from the site of injection.
The use of such long-circulating liposomes, that is, liposomes with a surface coating of hydrophilic polymer chains, such as polyethylene glycol (PEG) chains, for targeting has been proposed (Allen, et al., 1995; DeFrees, et al., 1996; Blume, et al., 1993; Klibanov, et al., 1992; Woodle, 1991; Zalipsky, 1993; Zalipsky, 1994; Zalipsky, 1995). In one approach, a ligand, such as an antibody, for targeting the liposomes is linked to the polar head group of lipids forming the liposome. The problem with this approach is that the ligand is covered by the PEG chains, interfering with the ligand's interaction with the target and reducing its effectiveness as a targeting agent.
In another approach, the targeting ligand is attached to the distal ends of the PEG chains forming the hydrophilic polymer coating (Klibanov, et al., 1992; Kirpotin, et al., 1992). While this approach improves targeting, since the targeting moiety is more exposed, the approach has drawbacks in that the PEG chains act to stabilize liposome, making release of the liposome's contents at the target site difficult and in that the attached moiety can compromise the extended blood circulation lifetime provided by the surface coating of hydrophilic polymer chains (Klibanov, et al., 1992).
For a variety of reasons, it may be desirable to shield all or at least a portion of the targeting moieties attached to the liposome until a desired biodistribution of the liposomes is achieved. If a high density of moieties is desired, and all of the targeting moieties in an exposed state on liposome surface, the presence of the moieties may limit the blood circulation time of the liposomes. Another problem with unshielded targeting moieties is that the moiety may direct liposomes to non-target surfaces or cells, before a desired biodistribution is reached.
Therefore, it is desirable to provide a therapeutic liposome composition including affinity moieties, e.g., targeting moieties, where all or at least a portion of the moieties are initially shielded from interaction with a target surface, but which can be unshielded when a desired biodistribution is reached.